Many chronic diseases of the brain could be treated with gene therapy. However, viral vectors do not cross the brain capillary wall, which forms the blood-brain barrier (BBS) in vivo. The proposed research advances a new, non-viral, trans-vascular approach to brain gene therapy, where an expression plasmid encoding the therapeutic gene is encapsulated in pegylated immunoliposomes or PILs. The PILs are nano-containers that are targeted across the BBB, and across the brain cell membrane (BCM), with a monoclonal antibody (MAb) to the transferrin receptor (TfR). The MAb to the TfR acts as a molecular Trojan horse, which ferries the gene across the BBB, and the BCM, by accessing the endogenous TfR-mediated transport systems within the BBB and the BCM. Because the gene can cross the BBB, the route of administration is non-invasive and requires only an intravenous administration. The trans-vascular route of delivery enables the gene to distribute to the entire volume of brain. The plasmid DNA is not integrated in the host genome, which is considered advantageous, since there is no risk of insertional mutagenesis. The plasmid DNA functions as an episome, and the persistence of expression of the exogenous gene is a function of the degradation of the plasmid by nuclear DNases. In prior work in an experimental model of Parkinson's disease (PD), it was possible to completely normalize striatal tyrosine hydroxylase (TH) activity with a single intravenous injection of PILs carrying a TH expression plasmid. The limiting factor in this approach is the limited duration of persistence of gene expression. Following the delivery of TH expression plasmid, the brain TH enzyme activity decays with a half-time of 6 days following the single intravenous injection. There is evidence that longer periods of gene expression are possible with the brain delivery of chromosomal derived forms of the TH gene. Genomic forms of the exogenous gene, as compared to cDNA forms of the gene, attract nuclear proteins forming mini-chromatin structures, which are less susceptible to DNase degradation of the exogenous plasmid. The present research will combine PIL brain gene targeting with chromosomal derived forms of the rat TH gene. Following cloning of the rat TH gene, novel chromosomal derived TH expression plasmids will be incorporated into TfRMAb-targeted PILs for delivery to brain of rats with experimental PD following intravenous administration of non-viral formulations. [unreadable] [unreadable] [unreadable]